Obesity is arguably the most important healthcare crisis affecting the US today. Obesity is associated with an increased risk for developing and dying from several types of cancer, including kidney cancer, but the causes of this heightened risk of death are currently unclear. We hypothesize that obesity diminishes the normal immunological processes that keep tumor growth in check and decreases the effectiveness of cancer immunotherapies. Prior studies have reported decreased anti-tumor immunity in the obese, but there is little mechanistic data to explain why this occurs, and a thorough understanding of the impact of obesity on immune function is lacking. We have begun to address this need by exploring the link between obesity and diminished anti-tumor immunity. Our 2012 publication was one of the first to demonstrate that obesity is associated with immunotherapeutic failure. In this application, our objective is to define the cellular and molecular basis for impaired anti-tumor immunity in obese mice and humans. Currently, the vast majority of pre-clinical cancer models use only lean mice, so they do not address the impact of obesity or other co-morbidities on anti- tumor immunity. Our long-term goal is to identify specific immunological defects that arise in response to the combination of obesity and tumor outgrowth, then leverage this information to develop effective immunotherapies for cancer patients. The rationale for our proposal is that by understanding the consequences of obesity on anti-tumor immunity, we will be able to optimize immunotherapies in future studies, thereby prolonging life expectancy and quality of life for patients with kidney cancer and other obesity- related cancers, such as melanoma and prostate cancer. In addition, our studies should reveal new obesity- related immunologic patterns that can act as predictive biomarkers for immunotherapy failure in patients with kidney cancer and other obesity-related cancers. Overall Hypothesis: Obesity causes reversible defects in DC and T cell-based adaptive immunity to kidney cancer, resulting in immunotherapeutic failure and heightened mortality from uncontrolled tumor growth. Aim 1. Identify obesity-induced alterations in T cell priming and effector function in mice with kidney cancer. Aim 2. Define obesity-induced alterations in immunosuppressive cell populations in mice with kidney cancer. Aim 3. Identify obesity-related changes in anti-tumor immunity in obese human subjects with renal tumors. We expect our findings to substantially advance fundamental understanding of the ways in which obesity alters anti-tumor immunity, thereby promoting uncontrolled tumor growth and mortality from kidney cancer and other obesity-related cancers. The knowledge we gain during the course of these studies will provide a framework for future translational research aimed at improving the effectiveness of immunotherapies in obese and lean cancer patients.!